The New Kids on the Block

The N ew Kids on th e Bloc k Recently Characterized Soft Tissue Tumors Nicole N. Riddle, MDa, Jerad M. Gardner, MDb,c,* KEYWORDS  Soft tissue pathology  Sarcoma  Molecular  Liposarcoma  ALK

S

oft tissue pathology is a rapidly changing subspecialty. New entities are described relatively often, and new molecular findings for soft tissue tumors are reported in the literature almost every month. This article summarizes the major features and diagnostic approach to several recently characterized entities: superficial CD34positive fibroblastic tumor, fibrosarcoma-like lipomatous neoplasm, angiofibroma of soft tissue, low-grade sinonasal sarcoma with neural and myogenic features, malignant gastrointestinal neuroectodermal tumor, hemosiderotic fibrolipomatous tumor, and epithelioid inflammatory myofibroblastic sarcoma. Additionally, the article also provides a summary table of recent molecular findings in soft tissue tumors.

OVERVIEW Soft tissue pathology is a rapidly changing subspecialty. Novel molecular findings are published monthly, rivaling even hematopathology in the speed with which the genetic underpinnings of neoplasia are probed. Tumors that were previously known under one rubric are reclassified with relative frequency. Lesions that for decades were thought to be reactive now are discovered to possess gene rearrangements (e.g. – nodular fasciitis), and the features of previously unknown or incompletely described tumors are coalesced and synthesized into new entities. The relative rarity of soft tissue tumors only adds to the challenge

of keeping abreast of all of these advances. In this article, we attempt to highlight some of the more pertinent soft tissue tumors that have been recently characterized and to make them more accessible to the general surgical pathologist. We also provide a brief summary of significant molecular findings, not only in these newly described tumors, but also in older entities for which molecular abnormalities have only recently been elucidated.

SUPERFICIAL CD34-POSITIVE FIBROBLASTIC TUMOR Carter and colleagues1 characterized superficial CD34-positive fibroblastic tumor in 2013. They described 18 cases of a tumor with unique characteristics: striking nuclear pleomorphism, paradoxically rare mitotic activity, indolent behavior, and diffuse CD34 expression. All cases occurred in adults and all presented as a slow-growing supra-fascial mass of 10 cm or less (mean: 4.1 cm), most commonly in the lower extremity. Awareness of this entity is important, as there is a tendency for overdiagnosis as a pleomorphic sarcoma in light of the nuclear atypia, even though most cases do not recur or metastasize. Of 13 patients with follow-up (median: 24 months), there were no local recurrences, no distant metastases, and no death from disease; 1 patient had a regional lymph node metastasis 7 years after presentation. In light of this, Carter and colleagues1 suggested this entity be considered as a lesion of borderline malignancy.

a Department of Pathology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, MC7750, San Antonio, TX 78229, USA; b Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street #517, Room S4/11, Little Rock, AR 72205, USA; c Department of Dermatology, University of Arkansas for Medical Sciences, 4301 West Markham Street #517, Room S4/11, Little Rock, AR 72205, USA * Corresponding author. University of Arkansas for Medical Sciences, 4301 West Markham Street #517, Room S4/11, Little Rock, AR 72205. E-mail address: [email protected]

Surgical Pathology 8 (2015) 467–491 http://dx.doi.org/10.1016/j.path.2015.05.003 1875-9181/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

surgpath.theclinics.com

ABSTRACT

468

Riddle & Gardner PATHOLOGIC FEATURES Superficial CD34-positive fibroblastic tumor is a subcutaneous mass with little or no involvement of the deep musculature. It is often relatively circumscribed, although it may show peripheral infiltrative growth. Most tumor cells display marked nuclear pleomorphism with hyperchromasia and multiple large inclusion-like nucleoli as well as cytoplasmic nuclear pseudoinclusions. The cells are

spindled to epithelioid with abundant eosinophilic often granular cytoplasm and are arranged into hypercellular sheets or fascicles (Fig. 1A, B). Xanthomatous foamy tumor cells are commonly seen, and mixed inflammation is often present. Small vessels are arranged in a plexiform pattern in the background of the tumor, but large ectatic hyalinized vessels, like those of pleomorphic hyalinizing angiectactic tumor (PHAT), are not seen. Despite the extreme degree of nuclear atypia, mitotic figures Fig. 1. (A) Superficial CD34-positive fibroblastic tumor is composed of sheets of pleomorphic spindle cells. (B) Superficial CD34-positive fibroblastic tumor: there is marked nuclear pleomorphism but mitoses are rare. Tumor cells display abundant eosinophilic cytoplasm.

New Soft Tissue Tumors Fig. 1. (continued). (C) Diffuse strong CD34 expression in tumor cells is a defining feature of superficial CD34-positive fibroblastic tumor. (D) Focal cytokeratin expression is present in most superficial CD34-positive fibroblastic tumors. (Courtesy of [A, B] Dr Scott Lauer, Omaha, NE; and [C, D] Dr Andrew Folpe, Rochester, MN.)

are very rare (<1/50 high-power fields [HPFs]) in most cases, and atypical forms are absent. Focal necrosis has been reported in only 1 case.1 By immunohistochemistry, this entity is diffusely and strongly positive for CD34 in all cases (see Fig. 1C). Most (69%) cases also display focal cytokeratin expression (see Fig. 1D). FLI-1, ERG, S100 protein, desmin, smooth muscle actin, and TP53 are all negative, Ki-67 proliferative index is less than 1%, and nuclear INI-1 (SMARCB1) expression is retained. Cases tested by fluorescence in

situ hybridization (FISH) for TGFBR3 and/or MGEA5 rearrangements have all been negative.1

DIFFERENTIAL DIAGNOSIS This entity may be easily confused with undifferentiated pleomorphic sarcoma (formerly “malignant fibrous histiocytoma”), myxofibrosarcoma, or atypical fibroxanthoma (AFX) because of the striking nuclear pleomorphism. Yet both the diffuse CD34 expression and the very low mitotic rate of

469

470

Riddle & Gardner superficial CD34-positive fibroblastic tumor would be distinctly unusual for those entities. Furthermore, AFX usually occurs in sun-exposed sites, such as the head and neck, rather than the lower extremity. Myxoinflammatory fibroblastic sarcoma (MIFS) has bizarre pleomorphism, large inclusion-like nucleoli, and relatively low mitotic activity, all features similar to superficial CD34-positive fibroblastic tumor. But in contrast, most MIFS occur in acral sites, lack diffuse CD34 expression, possess more abundant myxoid background, and display rearrangements of TGFBR3 and/or MGEA5 genes.2 PHAT is also in the differential diagnosis, as it has marked nuclear pleomorphism but low mitotic activity, but the characteristic ectatic hyalinized blood vessels and abundant hemosiderin deposition that typify PHAT are lacking in superficial CD34-positive fibroblastic tumor. Other entities potentially in the differential, such as intermediate or malignant vascular tumors, epithelioid sarcoma, or malignant granular cell tumor can usually be easily excluded by immunohistochemistry.1

Key Pathologic Features

FIBROSARCOMA-LIKE LIPOMATOUS NEOPLASM In 2013, Deyrup and colleagues3 revisited the concept of “spindle cell liposarcoma,” a term that in their opinion actually represents a heterogeneous group of tumors, including variants of welldifferentiated liposarcoma, myxoid liposarcoma, and even spindle cell lipoma based on their analysis of previous publications on this topic. After excluding those entities by molecular analysis, they describe 12 cases of what they propose to represent a distinct group of low-grade adipocytic neoplasm with prominent spindle cell component that they termed “fibrosarcoma-like lipomatous neoplasm” in light of a tendency for parallel fascicular arrangement of the spindle cells. Most of these tumors arose in adults (mean age: 50 years), although 2 cases were in adolescents. They presented as superficial or deep soft tissue masses with a wide size range (mean: 7.5 cm) arising in the groin and paratesticular region, as well as the buttock, thigh, flank, and shoulder. No recurrence or metastasis was identified in any of these patients (mean follow-up time: 68 months), suggesting that perhaps “liposarcoma” is not an appropriate term for this tumor, based on current data.

1. Supra-fascial mass, less than 10 cm 2. Striking pleomorphism but low mitotic rate (<1 per 50 HPFs) 3. Diffuse strong CD34 expression (always), focal cytokeratin expression (often)

Main Differential Diagnosis 1. Undifferentiated pleomorphic sarcoma 2. Myxofibrosarcoma 3. Atypical fibroxanthoma 4. Myxoinflammatory fibroblastic sarcoma 5. Pleomorphic hyalinizing angiectactic tumor

Pitfalls

! Marked pleomorphism mimics high-grade pleomorphic sarcomas ! CD34 and cytokeratin expression could lead to confusion with vascular and/or epithelial tumors

PATHOLOGIC FEATURES Fibrosarcoma-like lipomatous neoplasm is a vaguely multinodular tumor with variable cellularity (Fig. 2A). It is composed of relatively uniform fibroblast-like spindle cells arranged parallel to one another in a myxoid background with an arborizing capillary vasculature (see Fig. 2B, C). The characteristic finding is the presence of a wide range of adipocytic differentiation apparently recapitulating the various embryologic steps of fat development (see Fig. 2D). This includes preadipocyte-like cells that resemble bland fibroblasts with no obvious lipid droplet, as well as more differentiated spindle cells that display minute cytoplasmic lipid droplets. In some of these, the lipid droplets are larger and indent the nucleus, forming univacuolated (“ice cream cone”) and bivacuolated (“hourglass”) spindled lipoblasts (see Fig. 2E). Signet ring lipoblasts, similar to those of myxoid liposarcoma, also may be present. Variable amounts of these different lipoblasts are present in each case.3 These lipoblasts have bland and uniform nuclei without significant atypia; pleomorphic lipoblasts are not seen.

DIFFERENTIAL DIAGNOSIS The major differential diagnoses are welldifferentiated liposarcoma/atypical lipomatous

New Soft Tissue Tumors Fig. 2. (A) Fibrosarcoma-like lipomatous neoplasm is a multinodular tumor with variable cellularity. (B) Fibrosarcomalike lipomatous neoplasm is composed of relatively uniform fibroblast-like spindle cells in a myxoid background with an arborizing capillary vasculature. (C) The fibroblast-like spindle cells are often arranged parallel to one another in fibrosarcoma-like lipomatous neoplasm.

471

472

Riddle & Gardner Fig. 2. (continued). (D) The characteristic finding in fibrosarcoma-like lipomatous neoplasm is the presence of a wide range of adipocytic differentiation recapitulating the various embryologic steps of fat development. (E) Univacuolated (“ice cream cone”) and bivacuolated (“hourglass”) spindled lipoblasts are often seen in fibrosarcoma-like lipomatous neoplasm.

tumor (WDL/ALT), myxoid liposarcoma, and spindle cell lipoma. Fibrosarcoma-like lipomatous neoplasm certainly may have overlapping morphologic features with all of these entities.

Fortunately, molecular analysis can usually easily exclude these possibilities. WDL/ALT possesses amplification of 12q13-15, including the MDM2 and CDK4 genes. Myxoid liposarcoma has

New Soft Tissue Tumors characteristic translocations resulting in rearrangement of DDIT3. Spindle cell lipoma displays uniform loss of chromosome 13 and frequent losses of chromosomes 16 and 6. FISH or other molecular techniques can detect these molecular signatures. In contrast, fibrosarcoma-like lipomatous neoplasm is negative for all of these molecular abnormalities and also displays a flat profile on array comparative genomic hybridization analysis with no identifiable chromosomal gains or losses.3

Key Pathologic Features

1. Uniform fibroblast-like spindle cells arranged in parallel 2. Myxoid background with arborizing thin vessels 3. Wide range of lipoblasts, including signet ring and spindled univacuolated/bivacuolated cells

Main Differential Diagnosis

can either occur as solitary facial lesions in older adults (fibrous papule) or as multiple facial lesions in young patients with tuberous sclerosis (so-called by the misnomer “adenoma sebaceum”). In 2012, Marin˜o-Enrı´quez and Fletcher4 described 37 cases of a previously undescribed soft tissue tumor composed of bland spindle cells and abundant branched vessels that they termed “angiofibroma of soft tissue.” The tumors they described are clearly quite distinct histologically and molecularly from these other types of angiofibroma, and are also unlike any other previously described soft tissue tumor. Several additional case reports and small series published since their initial description further support that this lesion is a new and distinct entity.5–8 Angiofibroma of soft tissue is a slowgrowing tumor of the subcutis or deep soft tissue most commonly arising in the extremities (lower > upper) of adults, or, less frequently, children/adolescents. There is a roughly 2:1 female predominance. Most are well-circumscribed lesions with a median size of 3.5 cm (range: 1.2– 12.0 cm). Although the histologic features of this tumor, particularly the prominent branching vessels, may lead to diagnostic confusion with several forms of sarcoma, angiofibroma of soft tissue is a benign neoplasm that may occasionally recur locally (14%) but does not metastasize.4

1. Well-differentiated liposarcoma/atypical lipomatous tumor (WDL/ALT)

PATHOLOGIC FEATURES

2. Myxoid liposarcoma

Angiofibroma of soft tissue is composed of small spindle cells with bland uniform nuclei. These are set in a variably myxoid and collagenous background that displays numerous small branching blood vessels (Fig. 3A–C). The vascular pattern bears some resemblance to that of myxoid liposarcoma, except that in angiofibroma of soft tissue, the vessels are much more numerous and not as thin and delicate as in myxoid liposarcoma (see Fig. 3D, E). Lesser numbers of larger vessels are also present, often with ectatic, staghorn, hemangiopericytoma-like appearance. The tumor cells lack significant cytologic atypia, and mitoses are usually infrequent (<1 per 10 HPFs), although in a minority of cases may be more prominent (up to 4 per 10 HPFs); atypical mitoses are absent. Focal degenerative changes are occasionally seen, including ischemic necrosis, edema, or mild degenerative atypia.4 On immunohistochemistry, epithelial membrane antigen (EMA) is positive in nearly half of cases, usually only in scattered cells but rarely diffusely. Focal staining for desmin, smooth muscle actin (SMA), or CD34 may be seen in a subset of cases, but S100 protein is negative.4 Angiofibroma of soft tissue has a unique molecular signature: t(5;8)

3. Spindle cell lipoma

Pitfalls

! Can be easily confused histologically with more aggressive entities (myxoid or welldifferentiated liposarcomas) ! Literature regarding “spindle cell liposarcoma” can be confusing, as a variety of different tumors have been described under the same rubric

ANGIOFIBROMA OF SOFT TISSUE Several entities are referred to as “angiofibroma” in pathology: nasopharyngeal angiofibroma, which typically occurs in the nasal cavity of adolescent males; cellular angiofibroma, which occurs in the genital region and is likely a close relative of spindle cell lipoma; and angiofibroma of the skin, which

473

474

Riddle & Gardner Fig. 3. (A) Angiofibroma of soft tissue displays a variably myxoid and collagenous background as well as variable cellularity. The numerous small branching vessels are visible even from low magnification. (B) More cellular collagenous areas are seen in the upper right of this image of angiofibroma of soft tissue, whereas the bottom left displays less cellularity and a more myxoid and edematous background. Most of the numerous vessels are small and plexiform, although occasional larger ectatic hemangiopericytoma-like vessels are also present. (C) The spindle cells in angiofibroma of soft tissue have small bland uniform nuclei. There is minimal cytologic atypia, and mitoses are usually infrequent.

New Soft Tissue Tumors Fig. 3. (continued). (D) The thin branching vessels, intervening small uniform spindle cells, and myxoid background in some areas of angiofibroma of soft tissue may bear some resemblance to myxoid liposarcoma. (E) Although their vascular patterns are similar, in angiofibroma of soft tissue the vessels are usually much more numerous and not quite as thin and delicate as in myxoid liposarcoma. (Courtesy of Dr Scott Lauer, Omaha, NE.)

(p15;q13), resulting in fusion of the genes AHRR and NCOA2. This translocation can be detected by conventional cytogenetic karyotyping, reverse-transcriptase polymerase chain reaction (RT-PCR), or break-apart FISH.4,5,8,9

DIFFERENTIAL DIAGNOSIS The differential diagnosis most notably includes myxoid liposarcoma, low-grade fibromyxoid

sarcoma (LGFMS), solitary fibrous tumor (SFT), low-grade myxofibrosarcoma, and cellular angiofibroma. Myxoid liposarcoma is perhaps the most important of these in light of the relative similarity in the vascular pattern of both tumors and the vastly different treatment and prognosis. As mentioned previously, the vessels of myxoid liposarcoma are much more thin and delicate and fewer in number than those of angiofibroma of soft tissue. Furthermore, myxoid liposarcoma has

475

476

Riddle & Gardner characteristic translocations, resulting in rearrangement of DDIT3. LGFMS enters the differential because it also possesses bland spindle cells set in a variably myxoid and collagenous background, but LGFMS lacks the prominent plexiform vascular pattern seen in angiofibroma of soft tissue. Additionally, LGFMS usually expresses the relatively specific immunohistochemical marker MUC4 and also has characteristic translocations resulting in fusions of FUS and either CREB3L1 or CREB3L2.10 SFT has several overlapping histologic features with angiofibroma of soft tissue. Although both entities often possess ectatic staghorn vessels, these are more frequent in SFT and not typically accompanied by numerous thin branching vessels. SFT usually displays strong diffuse CD34 expression, nuclear STAT6 expression, and recurrent NAB2-STAT6 gene fusions.5,11 Low-grade myxofibrosarcoma has a myxoid background but usually with long curvilinear vessels rather than abundant plexiform vessels; it also differs from angiofibroma of soft tissue by the presence of overtly malignant features, such as prominent nuclear pleomorphism and mitotic activity. Cellular angiofibroma is similar in name, but unlike angiofibroma of soft tissue, it occurs mostly in the genital region, has thicker vessels with less branching, and has histologic and molecular features similar to spindle cell lipoma.4,8

Key Pathologic Features

1. Bland uniform spindle cells with minimal atypia 2. Variably myxoid and collagenous background 3. Numerous branching thin-walled blood vessels 4. t(5;8) AHRR-NCOA2 gene fusion

Main Differential Diagnosis 1. Myxoid liposarcoma 2. Low-grade fibromyxoid sarcoma 3. Solitary fibrous tumor 4. Low-grade myxofibrosarcoma 5. Cellular angiofibroma

Pitfall

! Can be confused with several other more aggressive soft tissue neoplasms

LOW-GRADE SINONASAL SARCOMA WITH NEURAL AND MYOGENIC FEATURES Low-grade sinonasal sarcoma with neural and myogenic features (LGSSNMF), also known as biphenotypic sinonasal sarcoma, is a recently described entity based on review of sinonasal sarcomas from several decades of cases and consults.12,13 Sinonasal sarcomas in general are very rare and oftentimes these lesions were believed to be examples of known entities (fibrosarcoma, malignant peripheral nerve sheath tumor [MPNST], synovial sarcoma). However, these cases were found to all have similar characteristic histology, along with evidence of neural and myogenic differentiation. The clinical presentation is similar to other sinonasal neoplasms and includes general features of sinusitis: difficulty breathing, facial pressure, congestion, and, rarely, facial pain. The age range is 24 to 85 years (mean: 52 years), and there is female predominance in the original series (21 women, 7 men). The lesion most commonly affects multiple sites, including the nasal cavity proper (54%) and ethmoid sinus (57%); extension into the orbit (25%) and cribriform plate (11%) were not uncommon. One tumor extended into the cranial vault. Local recurrence is common, but metastases or mortality from disease have not yet been reported.12

PATHOLOGIC FEATURES Lewis and colleagues12 defined the inclusion criteria as highly cellular, infiltrative spindle cell neoplasm with uniform, elongated nuclei and at least focal S100 positivity. Specimens are typically received as multiple polypoid tan/red fragments measuring up to 4 cm in greatest dimension, possibly more firm than the typical inflammatory nasal polyp, but otherwise with no distinctive features. The histologic features demonstrate a poorly circumscribed, infiltrative, cellular neoplasm composed of bland spindle cells often arranged in short fascicles reminiscent of a “herringbone” pattern (Fig. 4A–D). Wavy or buckled nuclei are often identified (see Fig. 4E). No significant atypia is present; however, a minority of tumors will show focal rhabdomyoblastic-type cells with larger hyperchromatic nuclei and abundant eosinophilic

New Soft Tissue Tumors Fig. 4. (A) LGSSNMF is a cellular spindle cell proliferation in the nasal submucosa. (B) LGSSNMF is composed of bland spindle cells arranged in hypercellular fascicles. (C) The hypercellular fascicles in LGSSNMF often display an intersecting herringbone pattern, a finding that may cause confusion with synovial sarcoma or malignant peripheral nerve sheath tumor.

477

478

Riddle & Gardner Fig. 4. (continued). (D) The spindle cells of LGSSNMF are bland and uniform with minimal atypia. Mitoses are infrequent. (E) Wavy or buckled nuclei are often identified in LGSSNMF, imparting a neural appearance. (Courtesy of [A–D] Dr Scott Lauer, Omaha, NE; and [E] Dr Raul Gonzalez, Rochester, NY.)

cytoplasm. Mitoses are infrequent. Vessels are typically not prominent; however, a minority of cases may show areas of hemangiopericytic-patterned vasculature. No dense or ropey collagen is present, with the intercellular collagen being scanty to moderate and arranged in delicate strands. A characteristic finding present in most cases is a benign proliferation of the surface respiratory epithelium leading to invaginations of small glands or cystic

spaces. These glandular structures are often admixed among the tumor cells and impart a histologic image similar to adenosarcoma of the female genital tract. It is important to be aware of this associated proliferation, as shallow biopsies may be misdiagnosed as inverted papilloma. The immunohistochemical features are characteristic in that they have S100 positivity in addition to SMA and/or muscle-specific actin (MSA). The

New Soft Tissue Tumors staining of S100 and muscle markers is often diffuse, but sometime patchy or only in isolated tumor cells. Other stains that may be rarely focally positive are CD34, desmin, EMA, and cytokeratin AE1/3. No estrogen receptor (ER), progesterone receptor (PR), or myogenin staining is seen. A recent study by Wang and colleagues13 found PAX3 rearrangement by FISH in 96% of LGSSNMF (n 5 25); 79% of these cases were positive for PAX3-MAML3 fusion by RT-PCR.12 Of note, one recently reported case showed only focal SMA and MSA, but did have staining for caldesmon and b-catenin, and the electron microscopy findings were also different.14 The investigators raised the possibility that maybe the tumor has fibroblastic differentiation instead of myogenic differentiation. Given that the first series did not perform b-catenin and the later series did not do molecular studies, it is possible that these represent tumors with variable myofibroblastic differentiation on a spectrum or possibly 2 different tumor types.

DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis for LGSSNMF includes mainly fibrosarcoma, MPNST, and monophasic synovial sarcoma, and possibly glomangiopericytoma, SFT, and cellular schwannoma. Indeed, many of these cases have probably been reported as such in the past. In general, immunohistochemistry should be helpful in distinguishing these lesions. However, given the potentially focal/ patchy nature of both S100 and muscle markers, conceivably a small biopsy could lack one or both markers, leading to an incorrect diagnosis. The rare and focal cytokeratin staining may lead one to think of synovial sarcoma, but all LGSSNMF tested have been negative for SS18 (SYT) translocations, so FISH would prove helpful in this differential.12

Key Pathologic Features

1. Poorly circumscribed, infiltrative 2. Highly cellular, bland spindle cells, in vague “herringbone” pattern, without atypia or frequent mitoses 3. Positivity for S100 and muscle markers (SMA, MSA) 4. Benign proliferation of respiratory epithelium with variable admixture with tumor cells 5. Rarely: rhabdomyoblastic differentiation, hemangiopericytic vascular pattern

Main Differential Diagnosis 1. Fibrosarcoma 2. Malignant peripheral nerve sheath tumor 3. Synovial sarcoma, monophasic-type

Pitfalls

! Patchy immunohistochemical staining for S100 and actins, which may not be present on small biopsies ! Overlying epithelial proliferation may lead to misdiagnosis as inverted papilloma ! Focal cytokeratin expression may lead to misdiagnosis as monophasic synovial sarcoma

MALIGNANT GASTROINTESTINAL NEUROECTODERMAL TUMOR Malignant gastrointestinal neuroectodermal tumor (GNET) is a rare, aggressive tumor of the gastrointestinal (GI) tract that has previously been referred to as “clear cell sarcoma-like tumor of the GI tract with osteoclast-like giant cells.”15–19 The name was proposed by Stockman and colleagues15 after a review of 16 cases showed histologic features, immunohistochemical pattern, and molecular findings similar to clear cell sarcoma of soft tissue, but with distinct differences, including no evidence of melanocytic differentiation.20 GNET has an equal male/female distribution with an age range of 17 to 77 years (mean, 42 years). Patients often present with abdominal pain, intestinal obstruction, or an abdominal mass, with anorexia, anemia, weight loss, high-grade fever, and weakness also reported. Tumors are more common in the small bowel, but also may occur in the stomach and colon. If the tumor can be completely removed, the prognosis may be good; however, metastases are common (over 50%), often to liver and lymph nodes. In the Stockman and colleagues15 series, 50% of patients died of disease (most within 2–3 years), and most remaining living patients had regional and liver metastasis.

479

480

Riddle & Gardner PATHOLOGIC FEATURES Grossly, the lesions range in size from 2 to 15 cm (mean, 5.2 cm; median, 3.8 cm) and are firm, solid, tan-white lobulated masses with focal areas of hemorrhage and necrosis. Lesions are based primarily in the submucosa and muscularis propria and may grow in an exophytic fashion protruding into the bowel lumen, circumferentially mimicking carcinoma, or transmurally with overlying mucosal ulceration (Fig. 5A).15 Histologically, the lesion consists of diffuse sheets or nests of uniform, predominately epithelioid/polygonal cells with variable amounts of eosinophilic to clear cytoplasm (see Fig. 5B–D). Scattered oval-to-spindle cells are variably seen. The nuclei are vesicular with marginated chromatin, indistinct to small nucleoli and scattered intranuclear cytoplasmic inclusions (see Fig. 5E). Mitoses vary from 0 to 20 per 10 HPFs (mean, 6 per 10 HPFs). Focal pseudoalveolar, pseudopapillary, microcystic, fascicular, or cord-like patterns may be seen.15 Immunohistochemically, the tumors appear to be uniformly positive for S100, SOX10, and vimentin. S100 positivity is typically strong and diffuse, although rarely may be focal. Neuroendocrine markers are variably present (CD56, 70%; synaptophysin, 56%; NB84, 50%; NSE, 45%; and neurofilament, 14%). Notably, the melanocytic markers (HMB-45, melan A, tyrosinase, and MiTF) and GI stromal tumor (GIST) markers (DOG1, CD34, and CD117) are all negative. Other negative markers are glial fibrillary acidic protein, desmin, SMA, CD99, and NeuN, and epithelial markers (very rare cases may show focal CAM5.2 positivity). Ki-67 is often 20% to 30%.15

FISH analysis will be positive for EWSR1 break apart in 86% of cases. The fusion genes are typically CREB1 or ATF1. These translocations are not unique and may be seen in clear cell sarcoma of soft tissue and angiomatoid fibrous histiocytoma. FUS rearrangements are not present in GNET.15

DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis for GNET includes GIST, monophasic synovial sarcoma, melanoma, soft tissue clear cell sarcoma involving the GI tract, and, rarely, variants of perivascular epithelioid cell tumor (PEComa) and epithelioid MPNST. It is important to distinguish GNET from these entities, as treatment and prognosis may be quite different. A thorough immunohistochemical and/or molecular workup can usually sort these out (see Main Differential Diagnosis box).

Key Pathologic Features

1. Epithelioid/polygonal cells with variable amount of eosinophilic cytoplasm 2. Vesicular nuclei with chromatin margination and scattered intranuclear cytoplasmic inclusions 3. S100, SOX10, and neuroendocrine markers positive, but specific melanocytic markers negative 4. EWSR1 translocation

Main Differential Diagnosis

S100 SOX10 MART1/HMB-45 Actin/Desmin CK/EMA CD117 DOG1 EWSR1a SS18a GNET CCS Melanoma GIST SS21 PEComa22,23 E-MPNST

1 1 1 1/ 1/ 1

1 1 1

1 1

1 1

1/ 1 1

1

1 1

1

1

Note: This table shows typical immunophenotype and molecular profile for these entities; exceptions exist. Abbreviations: 1, usually positive; , usually negative; 1/ , sometimes positive; CCS, soft tissue clear cell sarcoma involving GI tract; E-MPNST, epithelioid malignant peripheral nerve sheath tumor; GIST, gastrointestinal stromal tumor; GNET, gastrointestinal neuroectodermal tumor; PEComa, perivascular epithelioid cell tumor; SS, monophasic synovial sarcoma. a By break-apart FISH.

New Soft Tissue Tumors Fig. 5. (A) Malignant GNET is usually based primarily in the submucosa and muscularis propria and may grow in an exophytic fashion with overlying mucosal ulceration, as seen in this case. (B) GNET is composed of tumor cells arranged in sheets or nests that are sometimes divided by dense fibrous bands. (C) This example of GNET displays trabeculae of uniform eosinophilic cells with intervening dense fibrosis. The pattern is similar to that of clear cell sarcoma of soft tissue.

481

482

Riddle & Gardner Fig. 5. (continued). (D) GNET is composed of uniform epithelioid cells with variable amounts of clear or eosinophilic cytoplasm. (E) Tumor nuclei in GNET are vesicular with marginated chromatin and indistinct to small nucleoli. (Courtesy of [A, E] Dr Rhonda Yantiss, New York, NY; and [B–D] Dr Raul Gonzalez, Rochester, NY.)

Pitfalls

! Similar histology and chromosomal aberration as clear cell sarcoma of soft tissue; differs by absence of melanocytic marker expression, such as MART-1 and HMB-45 in GNET. ! GIST, a much more common GI tract tumor with more pathologist awareness, may have similar histologic appearance to GNET; misdiagnosis can be avoided by using a simple immunohistochemical panel.

New Soft Tissue Tumors

HEMOSIDEROTIC FIBROLIPOMATOUS TUMOR First described in 2000, hemosiderotic fibrolipomatous tumor (HFLT) was originally believed to be a reactive process.24 However, recent studies have shown a consistent t(1;10) abnormality and reports have been made of cases transforming into myxoinflammatory fibroblastic sarcoma (MIFS), as well as PHAT,25 thus confirming the neoplastic nature of this lesion.2,26–28 HFLT is a slow-growing, but locally aggressive lesion with a striking predilection for the foot/ankle region of middle-aged adults. However, reported ages range from 8 months to 74 years and locations have included the thigh, hand, and cheek. Local recurrence is common if HFLT is not fully removed. The initial series of patients had a high incidence of previous trauma leading to the belief that these were reactive lesions. But further reports have not shown a connection to previous trauma and indeed have supported occasional true malignant transformation.25,28–31

PATHOLOGIC FEATURES HFLT is grossly fatty/gelatinous and ranges in size from 1 to 19 cm. Histologically, it is an unencapsulated lesion with varying proportions of mature adipocytes with admixed fibroblastic spindle cells (Fig. 6A). A consistent feature is variable amounts of hemosiderin deposition, predominantly within macrophages in the spindled component, but also in the spindled cells proper. The spindle cell component often has a streaming, swirling, or honeycomb pattern and scattered osteoclast-like giant cells are common (see Fig. 6B–D). A lymphoplasmacytic inflammatory component is scattered throughout the lesion with occasional mast cells or eosinophils. Mitoses, atypia, and necrosis are rarely seen. Immunohistochemistry is not specific and includes positivity for CD34 and calponin and negativity for SMA, desmin, CD68, S100, and keratins.32 As referenced previously, several studies have shown translocations involving TGFBR3 and MGEA5 genes, a molecular signature shared with some cases of both PHAT and MIFS.2,25,27 HFLT appears to be a precursor lesion to PHAT, with many cases of PHAT having HFLT areas around the periphery.25,28 However, these areas of HFLT are very infrequently seen in association with classic MIFS.25,28 Rare cases of HFLT recurring as MIFS have been reported.30,31 In light of these findings, one proposal is that these entities might be grouped into the “TGFBR3-MGEA5 family of tumors.”25,28 Recent work by Zreik and colleagues25 (presented at the United States and Canadian Academy of Pathology [USCAP] Annual Meeting

2015 but not yet published) suggests that hybrid HFLT/MIFS lesions do not actually show classic features of MIFS and thus might be better regarded as “HFLT showing progression to myxoid sarcoma” rather than progression to bona fide MIFS; thus, they suggest that MIFS is likely unrelated to HFLT and PHAT. As evidenced by multiple presentations on this topic at the recent USCAP 2015 annual meeting in Boston, the relationship between HFLT, PHAT, and MIFS is a clearly a matter of ongoing debate and investigation.

DIFFERENTIAL DIAGNOSIS Based on the morphologic features and typical location, the differential for HFLT includes primarily plexiform fibrohistiocytic tumor, atypical lipomatous tumor, spindle cell lipoma, and giant cell tumor of soft tissue. In children, the differential would include lipofibromatosis and fibrous hamartoma of infancy, although this location would be uncommon for the latter. And in cases with minimal fat component, nodular fasciitis and fibrous histiocytoma may be a consideration. The presence of both hemosiderin deposition and admixed adipose tissue in HFLT would be unusual for most of these entities, but the distinction can sometimes be challenging, particularly on small biopsies.

Key Pathologic Features

1. Fascicles of fibroblastic spindle cells containing hemosiderin and hemosiderin-laden macrophages 2. Variable amounts of admixed adipose tissue 3. Osteoclast-like giant cells 4. No significant atypia, mitoses, or necrosis

Main Differential Diagnosis 1. Plexiform fibrohistiocytic tumor 2. Atypical lipomatous tumor 3. Spindle cell lipoma 4. Giant cell tumor of soft tissue 5. Children: lipofibromatosis, fibrous hamartoma of infancy 6. Minimal fatty component: nodular fasciitis, fibrous histiocytoma

483

484

Riddle & Gardner

Pitfalls

! No specific immunohistochemical pattern: CD34 and calponin positivity ! May be associated with pleomorphic hyalinizing angiectactic tumor or myxoinflammatory fibroblastic sarcoma.

EPITHELIOID INFLAMMATORY MYOFIBROBLASTIC SARCOMA Inflammatory myofibroblastic tumor (IMT) is a mesenchymal tumor of intermediate malignant potential composed of spindled myofibroblasts with admixed inflammation. It often displays ALK rearrangements with a variety of partner genes and diffuse cytoplasmic staining for ALK by immunohistochemistry. A rare epithelioid variant of IMT Fig. 6. (A) HFLT is an unencapsulated lesion with varying proportions of mature adipocytes with admixed fibroblastic spindle cells. (B) HFLT often has a honeycomb pattern with clusters of mature adipocytes surrounded by spindle cells. Hemosiderin deposition is a consistent finding.

New Soft Tissue Tumors Fig. 6. (continued). (C) The spindle cells of HFLT swirl and stream between mature adipocytes. There is minimal atypia or mitotic activity. (D) Hemosiderin is present both in the neoplastic spindle cells of HFLT and in background siderophages. (Courtesy of Dr Scott Lauer, Omaha, NE.)

with distinctive nuclear membrane or perinuclear ALK staining was recently described and termed “epithelioid inflammatory myofibroblastic sarcoma” (EIMS) in light of its more aggressive behavior than conventional IMT. EIMS has a marked male predominance and wide age range

(7 months–63 years, median 39 years).33 They are almost exclusively found in the abdominal cavity with a single report in the pleural cavity.34 The lesions range in size from 8 to 26 cm, and accordingly commonly present with abdominal pain and fullness and various gastrointestinal symptoms.35

485

486

Riddle & Gardner Lesions may be multifocal at the time of presentation.

PATHOLOGIC FEATURES Histologically, the tumors are composed predominantly of loose sheets of epithelioid-to-round cells set in a myxoid background with abundant mixed inflammation (Fig. 7A). The tumor cells have eosinophilic-to-amphophilic cytoplasm and large round vesicular nuclei with prominent nucleoli

(see Fig. 7B, C). Most cases have focal spindle cell areas. The inflammatory infiltrate may be neutrophilic or lymphocytic predominant, but plasma cells are typically conspicuously absent. Mitotic activity is variable (average rate: 4 per 10 HPFs), and necrosis may be present.33 EIMS essentially always displays ALK staining by immunohistochemistry, usually in a distinctive nuclear membrane pattern, or less commonly, a perinuclear cytoplasmic pattern (see Fig. 7D). Other commonly positive markers are CD30

Fig. 7. (A) EIMS is composed predominantly of loose sheets of epithelioid-to-round cells set in a myxoid background with abundant mixed inflammation. (B) The tumor cells in EIMS have eosinophilicto-amphophilic cytoplasm and large round vesicular nuclei with prominent nucleoli.

New Soft Tissue Tumors Fig. 7. (continued). (C) The background inflammatory cells are predominantly lymphocytes in this case of EIMS. The tumor cells have eosinophilicto-amphophilic cytoplasm and large round vesicular nuclei with prominent nucleoli. Mitoses are present. (D) EIMS essentially always displays ALK staining by immunohistochemistry, usually in a distinctive nuclear membrane pattern. (Courtesy of Dr Karen Fritchie, Rochester, MN.)

(100%), desmin (90%), and focal SMA (50%). S100, caldesmon, EMA, and keratins are uniformly negative.33 ALK gene rearrangement with RANBP2 has been reported in EIMS and this specific fusion appears to be related to the unique

nuclear membrane ALK staining pattern and the more aggressive behavior seen in this rare epithelioid variant of IMT.35 Importantly, there is new anecdotal evidence that these lesions may respond to ALK inhibitors.36

487

488

Riddle & Gardner DIFFERENTIAL DIAGNOSIS The diagnosis of EIMS may be very challenging given its rarity and lack of histologic similarity to typical IMT. The common differential includes anaplastic large cell lymphoma (ALCL), epithelioid leiomyosarcoma, rhabdomyosarcoma (RMS), and dedifferentiated liposarcoma (DDL), among others. The differential with ALCL may be especially difficult given the overlapping morphology and immunohistochemical pattern; however, desmin and nuclear membrane ALK staining are not present in ALCL. DDL may also mimic either IMT or EIMS, as it has vast histologic variations and may have associated inflammation; the presence of a well-differentiated liposarcoma component and MDM2 amplification by FISH can help confirm a diagnosis of DDL over EIMS. Alveolar rhabdomyosarcoma is desmin positive and often expresses ALK, but the cytologic features are that of a round blue cell neoplasm with relatively little cytoplasm, and myogenin, which is almost always strongly expressed in alveolar RMS, is negative in EIMS. For all of the entities in the

differential, a full immunohistochemical workup is essential, and molecular studies for ALK rearrangements can be done in particularly difficult cases.

Key Pathologic Features

1. Epithelioid cells with vesicular nuclei and prominent nucleoli 2. Myxoid stroma 3. Inflammatory infiltrate of either predominantly neutrophils or lymphocytes 4. ALK positivity in unique nuclear membrane or perinuclear cytoplasmic pattern 5. ALK gene rearrangement, often fused with RANBP2

Table 1 Recent molecular findings in soft tissue tumors Tumor Name

Molecular Findings

Angiofibroma of soft tissue Angiomatoid fibrous histiocytoma Chondroid lipoma EIMS and other IMT Ewing-like round cell sarcomas Glomus tumors (benign and malignant) GNET HFLT, MIFS, and PHATa Intimal sarcoma of heart and great vessels Low-grade fibromyxoid sarcoma LGSSNMF Nodular fasciitis Ossifying fibromyxoid tumor Phosphaturic mesenchymal tumor Spindle cell hemangioma Spindle cell rhabdomyosarcomas (adults) Spindle cell rhabdomyosarcoma (infants) Sclerosing epithelioid fibrosarcoma Solitary fibrous tumor

AHRR-NCOA2 fusion4,5,9 EWSR1-CREB1, EWSR1-ATF1, or FUS-ATF1 fusion37 C11orf95-MKL2 fusion38 ALK- RANBP2 fusion & other ALK rearrangements35,39,40 CIC-DUX4 fusion41–43 or BCOR-CCNB3 fusion44,45 MIR143-NOTCH fusions46 EWSR1-ATF1 or EWSR1-CREB1 fusion15 TGFBR3 & MGEA5 rearrangments2,25,27,28 MDM2 & CDK4 amplification (12q13-14)47–50 FUS-CREB3L2, FUS-CREB3L1, or EWSR1-CREB3L1 fusion51 PAX3-MAML3 fusion12,13 MYH9-USP6 fusion52 PHF1 rearrangements53–56 FN1-FGFR1 fusion57 IDH1 & IDH2 mutations58,59 MYOD1 mutation60,61 NCOA2 rearrangements with SRF or TEAD162 EWSR1-CREB3L1 fusion, FUS rearrangements rare63,64 NAB2-STAT6 fusion11

Abbreviations: EIMS, epithelioid inflammatory myofibroblastic sarcoma; GNET, malignant gastrointestinal neuroectodermal tumor; HFLT, hemosiderotic fibrolipomatous tumor; IMT, inflammatory myofibroblastic tumor; LGSSNMF, low-grade sinonasal sarcoma with neural and myogenic features; MIFS, myxoinflammatory myofibroblastic sarcoma; PHAT, pleomorphic hyalinizing angiectactic tumor. a The molecular findings and relationships among HFLT, MIFS, and PHAT are ongoing topics of debate and investigation.

New Soft Tissue Tumors

Main Differential Diagnosis 1. ALCL 2. Epithelioid leiomyosarcoma 3. Rhabdomyosarcoma 4. Dedifferentiated liposarcoma

Pitfalls

! Epithelioid histology is not classically associated with IMT or related entities and may lead the pathologist away from recognition of this unique aggressive variant of IMT ! Similar histology and immunohistochemical staining to ALCL

RECENT MOLECULAR FINDINGS IN SOFT TISSUE TUMORS In addition to the molecular findings associated with the novel entities discussed in this article, a variety of molecular alterations have been recently reported in many established soft tissue tumors, as well. Although space does not permit full discussion of each, we have attempted to summarize many of these in Table 1.

REFERENCES 1. Carter JM, Weiss SW, Linos K, et al. Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade mesenchymal neoplasm of intermediate (borderline) malignancy. Mod Pathol 2014;27:294–302. 2. Antonescu CR, Zhang L, Nielsen GP, et al. Consistent t(1;10) with rearrangements of TGFBR3 and MGEA5 in both myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Genes Chromosomes Cancer 2011;50:757–64. 3. Deyrup AT, Chibon F, Guillou L, et al. Fibrosarcomalike lipomatous neoplasm: a reappraisal of so-called spindle cell liposarcoma defining a unique lipomatous tumor unrelated to other liposarcomas. Am J Surg Pathol 2013;37:1373–8. 4. Marin˜o-Enrı´quez A, Fletcher CD. Angiofibroma of soft tissue: clinicopathologic characterization of a distinctive benign fibrovascular neoplasm in a series of 37 cases. Am J Surg Pathol 2012;36:500–8.

5. Sugita S, Aoyama T, Kondo K, et al. Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors. Hum Pathol 2014;45:1588–96. 6. Fukuda Y, Motoi T, Kato I, et al. Angiofibroma of soft tissue with fibrohistiocytic features and intratumor genetic heterogeneity of NCOA2 gene rearrangement revealed by chromogenic in situ hybridization: a case report. Pathol Int 2014;64:237–42. 7. Lee JJ, Bredella MA, Springfield DS, et al. Soft tissue angiofibroma: a case report. Skeletal Radiol 2014; 43:403–7. 8. Edgar MA, Lauer SR, Bridge JA, et al. Soft tissue angiofibroma: report of 2 cases of a recently described tumor. Hum Pathol 2013;44:438–41. 9. Jin Y, Moller E, Nord KH, et al. Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes. Genes Chromosomes Cancer 2012;51:510–20. 10. Doyle LA, Moller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011;35:733–41. 11. Robinson DR, Wu YM, Kalyana-Sundaram S, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet 2013;45:180–5. 12. Lewis JT, Oliveira AM, Nascimento AG, et al. Lowgrade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol 2012;36:517–25. 13. Wang X, Bledsoe KL, Graham RP, et al. Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet 2014;46:666–8. 14. Powers KA, Han LM, Chiu AG, et al. Low-grade sinonasal sarcoma with neural and myogenic features— diagnostic challenge and pathogenic insight. Oral Surg Oral Med Oral Pathol Oral Radiol 2015; 119(5):e265–9. 15. Stockman DL, Miettinen M, Suster S, et al. Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract. Am J Surg Pathol 2012;36:857–68. 16. Kosemehmetoglu K, Folpe AL. Clear cell sarcoma of tendons and aponeuroses, and osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: a review and update. J Clin Pathol 2010;63:416–23. 17. Friedrichs N, Testi MA, Moiraghi L, et al. Clear cell sarcoma-like tumor with osteoclast-like giant cells in the small bowel: further evidence for a new tumor entity. Int J Surg Pathol 2005;13:313–8. 18. Zambrano E, Reyes-Mugica M, Franchi A, et al. An osteoclast-rich tumor of the gastrointestinal tract

489

Riddle & Gardner

490

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

with features resembling clear cell sarcoma of soft parts: reports of 6 cases of a GIST simulator. Int J Surg Pathol 2003;11:75–81. Huang W, Zhang X, Li D, et al. Osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcoma of soft parts. Virchows Arch 2006;448:200–3. Antonescu CR, Nafa K, Segal NH, et al. EWSCREB1: a recurrent variant fusion in clear cell sarcoma–association with gastrointestinal location and absence of melanocytic differentiation. Clin Cancer Res 2006;12:5356–62. Karamchandani JR, Nielsen TO, van de Rijn M, et al. Sox10 and S100 in the diagnosis of soft-tissue neoplasms. Appl Immunohistochem Mol Morphol 2012; 20:445–50. Folpe AL, Mentzel T, Lehr HA, et al. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 2005;29:1558–75. Miettinen M, McCue PA, Sarlomo-Rikala M, et al. Sox10: a marker for not only schwannian and melanocytic neoplasms but also myoepithelial cell tumors of soft tissue: a systematic analysis of 5134 tumors. Am J Surg Pathol 2015;39(6):826–35. Marshall-Taylor C, Fanburg-Smith JC. Hemosiderotic fibrohistiocytic lipomatous lesion: ten cases of a previously undescribed fatty lesion of the foot/ ankle. Mod Pathol 2000;13:1192–9. Zreik RT, Carter JM, Sukov WR, et al. Myxoinflammatory fibroblastic sarcoma and hybrid hemosiderotic fibrolipomatous tumor/myxoinflammatory fibroblastic sarcoma: related or not? United States and Canadian Academy of Pathology Annual Meeting (platform presentation). Boston, March 23, 2015. Wettach GR, Boyd LJ, Lawce HJ, et al. Cytogenetic analysis of a hemosiderotic fibrolipomatous tumor. Cancer Genet Cytogenet 2008;182:140–3. Hallor KH, Sciot R, Staaf J, et al. Two genetic pathways, t(1;10) and amplification of 3p11-12, in myxoinflammatory fibroblastic sarcoma, haemosiderotic fibrolipomatous tumour, and morphologically similar lesions. J Pathol 2009;217:716–27. Carter JM, Sukov WR, Montgomery E, et al. TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms. Am J Surg Pathol 2014;38: 1182–992. Browne TJ, Fletcher CD. Haemosiderotic fibrolipomatous tumour (so-called haemosiderotic fibrohistiocytic lipomatous tumour): analysis of 13 new cases in support of a distinct entity. Histopathology 2006; 48:453–61. Solomon DA, Antonescu CR, Link TM, et al. Hemosiderotic fibrolipomatous tumor, not an entirely benign entity. Am J Surg Pathol 2013;37:1627–30.

31. Elco CP, Marino-Enriquez A, Abraham JA, et al. Hybrid myxoinflammatory fibroblastic sarcoma/hemosiderotic fibrolipomatous tumor: report of a case providing further evidence for a pathogenetic link. Am J Surg Pathol 2010;34:1723–7. 32. Fletcher CDM, Bridge JA, Hogendoorn PC, et al. WHO classification of tumours of soft tissue and bone. 4th edition. Lyon (France): World Health Organization; 2013. 33. Marino-Enriquez A, Wang WL, Roy A, et al. Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol 2011;35:135–44. 34. Kozu Y, Isaka M, Ohde Y, et al. Epithelioid inflammatory myofibroblastic sarcoma arising in the pleural cavity. Gen Thorac Cardiovasc Surg 2014;62:191–4. 35. Li J, Yin WH, Takeuchi K, et al. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: a report of two cases and literature review. Diagn Pathol 2013;8:147. 36. Kimbara S, Takeda K, Fukushima H, et al. A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. Jpn J Clin Oncol 2014;44:868–71. 37. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 2007;46:1051–60. 38. Huang D, Sumegi J, Dal Cin P, et al. C11orf95-MKL2 is the resulting fusion oncogene of t(11;16)(q13;p13) in chondroid lipoma. Genes Chromosomes Cancer 2010;49:810–8. 39. Lovly CM, Gupta A, Lipson D, et al. Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov 2014;4:889–95. 40. Takeuchi K, Soda M, Togashi Y, et al. Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1-ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clin Cancer Res 2011;17:3341–8. 41. Choi EY, Thomas DG, McHugh JB, et al. Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology. Am J Surg Pathol 2013;37:1379–86. 42. Graham C, Chilton-MacNeill S, Zielenska M, et al. The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum Pathol 2012;43:180–9. 43. Specht K, Sung YS, Zhang L, et al. Distinct transcriptional signature and immunoprofile of CICDUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 2014;53:622–33.

New Soft Tissue Tumors 44. Pierron G, Tirode F, Lucchesi C, et al. A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 2012;44:461–6. 45. Puls F, Niblett A, Marland G, et al. BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma. Am J Surg Pathol 2014;38:1307–18. 46. Mosquera JM, Sboner A, Zhang L, et al. Novel MIR143-NOTCH fusions in benign and malignant glomus tumors. Genes Chromosomes Cancer 2013;52:1075–87. 47. Bode-Lesniewska B, Zhao J, Speel EJ, et al. Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery. Virchows Arch 2001;438:57–65. 48. Neuville A, Collin F, Bruneval P, et al. Intimal sarcoma is the most frequent primary cardiac sarcoma: clinicopathologic and molecular retrospective analysis of 100 primary cardiac sarcomas. Am J Surg Pathol 2014;38:461–9. 49. Zhang H, Macdonald WD, Erickson-Johnson M, et al. Cytogenetic and molecular cytogenetic findings of intimal sarcoma. Cancer Genet Cytogenet 2007;179:146–9. 50. Zhao J, Roth J, Bode-Lesniewska B, et al. Combined comparative genomic hybridization and genomic microarray for detection of gene amplifications in pulmonary artery intimal sarcomas and adrenocortical tumors. Genes Chromosomes Cancer 2002; 34:48–57. 51. Lau PP, Lui PC, Lau GT, et al. EWSR1-CREB3L1 gene fusion: a novel alternative molecular aberration of low-grade fibromyxoid sarcoma. Am J Surg Pathol 2013;37:734–8. 52. Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest 2011;91:1427–33. 53. Antonescu CR, Sung YS, Chen CL, et al. Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors–molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes Chromosomes Cancer 2014;53:183–93.

54. Endo M, Kohashi K, Yamamoto H, et al. Ossifying fibromyxoid tumor presenting EP400-PHF1 fusion gene. Hum Pathol 2013;44:2603–8. 55. Gebre-Medhin S, Nord KH, Moller E, et al. Recurrent rearrangement of the PHF1 gene in ossifying fibromyxoid tumors. Am J Pathol 2012;181:1069–77. 56. Graham RP, Weiss SW, Sukov WR, et al. PHF1 rearrangements in ossifying fibromyxoid tumors of soft parts: a fluorescence in situ hybridization study of 41 cases with emphasis on the malignant variant. Am J Surg Pathol 2013;37:1751–5. 57. Lee JC, Jeng YM, Su SY, et al. Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol 2015;235:539–45. 58. Kurek KC, Pansuriya TC, van Ruler MA, et al. R132C IDH1 mutations are found in spindle cell hemangiomas and not in other vascular tumors or malformations. Am J Pathol 2013;182:1494–500. 59. Pansuriya TC, van Eijk R, d’Adamo P, et al. Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet 2011;43:1256–61. 60. Agaram NP, Chen CL, Zhang L, et al. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 2014;53:779–87. 61. Szuhai K, de Jong D, Leung WY, et al. Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol 2014;232:300–7. 62. Mosquera JM, Sboner A, Zhang L, et al. Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 2013;52:538–50. 63. Arbajian E, Puls F, Magnusson L, et al. Recurrent EWSR1-CREB3L1 gene fusions in sclerosing epithelioid fibrosarcoma. Am J Surg Pathol 2014;38: 801–8. 64. Wang WL, Evans HL, Meis JM, et al. FUS rearrangements are rare in ’pure’ sclerosing epithelioid fibrosarcoma. Mod Pathol 2012;25:846–53.

491